Dr. Tregellas? research career has focused on the neurobiology of schizophrenia, a leading cause of disability for Veterans. Much of this research is focused on low-level sensory processing deficits and hippocampal hyperactivity, which is now considered a core feature of the illness. In addition to work examining various contexts in which hippocampal hyperactivity is observed in schizophrenia, Dr. Tregellas has explored the effect of this activity on other cognitive processes and is actively engaged in therapeutic development. Initially with nicotinic agonists, and now with other potential therapeutic strategies, he is leading efforts to target hippocampal hyperactivity as a means to improve treatments for the symptoms of schizophrenia. In his current project, Dr. Tregellas is determining if low-lose levetiracetam, an anticonvulsant agent typically used to control seizures, may reduce hippocampal hyperactivity in patients. This strategy originally was motivated not only by the fact that levetiracetam effectively reduces neuronal excitability in epilepsy, but also that low doses of the agent were shown to reduce neuronal activity in individuals with mild cognitive impairment, who also show excessive activity in the hippocampus. After initial studies showing that the agent reduces a measure of neuronal excitability in a mouse model of schizophrenia, Dr. Tregellas is now in the initial stages of a human clinical trial to determine if levetiracetam can reduce hippocampal hyperactivity and improve cognition in Veterans with schizophrenia. This work is currently funded by a VA Merit Review Award and a VA Research Career Scientist Award. In addition to work examining the neurobiology of schizophrenia, Dr. Tregellas is also interested in understanding how current treatments for schizophrenia cause weight gain and metabolic problems in patients. Toward this end, he has an NIH R01 to study the neuronal processes of antipsychotic-induced weight gain, and to examine the effects of exercise on these processes in patients. Specifically, this study examines the neuronal effects of antipsychotics associated with a high risk of weight gain, compared to treatments associated with a low risk of weight gain. Coupled with this, Dr. Tregellas also is studying the effects of a 12-week exercise intervention on neuronal responses associated with food intake behavior. Related to this work, Dr. Tregellas also is interested in understanding the neurobiology of obesity in the general population. With his VA collaborator Dr. Marc Cornier, Dr. Tregellas has performed and published a series of studies examining differences in neuronal response in individuals prone or resistant to obesity. Many of these studies have examined responses to changes in energy intake or expenditure. In his current work on this topic, Dr. Tregellas is leveraging an observation from his schizophrenia work, that an alpha-7 nicotinic agonist causes reduced neuronal response in some of the same networks that he had previously found to be hyperactive in individuals with obesity. This finding, along with an observed effect of drug on weight in the schizophrenia work, led to an NIH R01-funded study of the effects of an alpha-7 nicotinic agonist on neurobiological and behavioral processes related to obesity in the general population. The aim of this work is to better understand the neurobiology of obesity and develop treatments to reduce its prevalence, a goal of vital importance to the VA.